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Inhibitors of (alpha-v)(beta-6) integrin

a technology of beta-v and beta-v, which is applied in the field of inhibitors of beta-v (beta-6) integrin, can solve the problems of not being able to achieve therapeutic success with orally bioavailable integrin inhibitors

Inactive Publication Date: 2018-08-30
MORPHIC THERAPEUTIC INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention is related to a compound of formula (I) and its use in treating various diseases or conditions such as idiopathic pulmonary fibrosis, diabetic nephropathy, and others. The compound has a unique structure and exhibits therapeutic effects. The technical effects include improved treatment outcomes and reduced side effects. The compound can be administered to patients in need.

Problems solved by technology

However, there has been a notable absence of therapeutic success with orally bioavailable integrin inhibitors.

Method used

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  • Inhibitors of (alpha-v)(beta-6) integrin
  • Inhibitors of (alpha-v)(beta-6) integrin
  • Inhibitors of (alpha-v)(beta-6) integrin

Examples

Experimental program
Comparison scheme
Effect test

example 1

on of 2-(4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)acetic acid (compound 1)

Step 1: tert-butyl 4-(1,8-naphthyridin-2-yl)piperidine-1-carboxylate

[0185]

[0186]A mixture of tert-butyl 4-acetylpiperidine-1-carboxylate (2.0 g, 8.80 mmol), 2-aminonicotinaldehyde (1.1 g, 8.80 mmol) and L-proline (2.0 g, 17.60 mmol) in EtOH (20 mL) was heated to reflux overnight. Solvent was removed in vacuo, and the residue was purified by silica gel column (pet ether:EtOAc=1:1) to give tert-butyl 4-(1,8-naphthyridin-2-yl)piperidine-1-carboxylate as a colorless oil (0.8 g). Yield 30% (100% purity, UV=214 nm, ESI 314.2 (M+H)+).

Step 2: tert-butyl 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)piperidine-1-carboxylate

[0187]

[0188]Tert-butyl 4-(1,8-naphthyridin-2-yl)piperidine-1-carboxylate (0.8 g, 2.56 mmol) was hydrogenated over Pd—C (100 mg, 10% on activated carbon) under balloon hydrogen in EtOH (20 mL) at room temperature overnight. The reaction was filtered through Ce...

example 2

on of 2-(2-oxo-4-(4-((5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl) piperidine-1-carbonyl)piperazin-1-yl)acetic acid (compound 2)

Step 1: tert-butyl 4-(2-methoxy-2-oxoethyl)-3-oxopiperazine-1-carboxylate

[0199]

[0200]To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (5.00 g, 25.0 mmol) in DMF (50 mL) at 0° C. was added NaH (60% in mineral oil, 1.20 g, 30.0 mmol). The mixture was stirred for 30 min, and then methyl 2-bromoacetate (2.60 mL, 27.5 mmol) was added. The reaction was stirred at room temperate for 16 hours, then quenched with H2O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether:EtOAc 5:1 to 2:1) to afford the desired compound as a colorless oil (4.0 g). Yield 59% (86% purity, UV=214 nm, ESI 217.0 (M+H)+).

Step 2: methyl 2-(2-oxopiperazin-1-yl)acetate

[0201]

[0202]Tert-butyl 4-(2-methoxy-2-oxoethyl)-3-oxopiperaz...

example 3

on of 2-(2-oxo-4-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)piperidine-1-carbonyl)piperidin-1-yl)acetic acid (compound 3)

[0207]Step 1: methyl 1-(2-tert-butoxy-2-oxoethyl)-2-oxopiperidine-4-carboxylate

[0208]To a solution of methyl 2-oxopiperidine-4-carboxylate (2.90 g, 18.4 mmol) in DMF (30 mL) at 0° C. was added NaH (60% in mineral oil, 886 mg, 22.1 mmol). The mixture was stirred for 30 min, and then tert-butyl 2-bromoacetate (4.32 g, 22.1 mmol) was added. The reaction was stirred at room temperature for 16 hours, then quenched with water (20 mL), and extracted with EtOAc (50 mL×5). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether:EtOAc 4:1) to give methyl 1-(2-tert-butoxy-2-oxoethyl)-2-oxopiperidine-4-carboxylate as a colorless oil (1.5 g). Yield 30% (90% purity, UV=214 nm, ESI 216.1 (M+H)+).

Step 2: 1-(2-tert-butoxy-2-oxoethyl)-2-oxopiperidine-4-carboxylic acid

[020...

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Abstract

Disclosed are small molecule inhibitors of αvβ6 integrin, and methods of using them to treat a number of diseases and conditions.

Description

RELATED APPLICATION[0001]This application claims benefit of priority to U.S. Provisional Patent Application No. 62 / 464,693, filed Feb. 28, 2017.BACKGROUND OF THE INVENTION[0002]The heterodimeric integrin family of receptors modulate cellular shape and cell adhesion to the extracellular matrix in response to extrinsic and intrinsic cues.[0003]Integrin signaling controls cell survival, cell cycle progression, cell differentiation, and cell migration.[0004]The integrin receptor exclusively can signal a cell bi-directionally, both “inside-out” and “outside-in.” Thus, they mediate cell migration by transmitting forces from the extracellular matrix to the cytoskeleton and regulate cytoskeletal organization to achieve shape changes needed during cell migration. RGD-binding integrins can bind to and activate TGF-β, and have recently been implicated in fibrotic disease.[0005]Integrins are expressed on the surface of most of human cells. Their pathology contributes to a diverse set of human d...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D401/12C07D471/04C07D519/00
CPCC07D401/12C07D519/00C07D471/04A61P11/00A61P3/10A61P13/12A61P1/16A61P35/00A61P37/06A61P31/16A61P9/00A61P43/00A61P19/02A61P25/08A61P35/02A61P37/02C07D471/08C07D487/08A61K31/4375C07D471/10A61K31/4545A61K31/496
Inventor HARRISON, BRYCE A.BURSAVICH, MATTHEW G.BREWER, MARKGERASYUTO, ALEKSEY I.HAHN, KRISTOPHER N.KONZE, KYLE D.LIN, FU-YANGLIPPA, BLAISE S.LUGOVSKOY, ALEXEY A.ROGERS, BRUCE N.SVENSSON, MATS A.TROAST, DAWN M.
Owner MORPHIC THERAPEUTIC INC
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